Cytotoxic T lymphocytes (CTL) have been found to mediate protection in vivo against certain virus-induced diseases, including some caused by retroviruses (1-3). This defense mechanism might be particularly relevant against HIV, which can spread through cell-cell contact, and thus may not be accessible to antibody neutralization. Indeed, CD8+ cells have been shown to inhibit growth of HIV or SIV in cells of infected patients or monkeys (4,5). Efforts have thus been directed at studying the CTL response against different proteins of HIV. Human CD3+8+ CTL specific for the envelope glycoprotein gp160 have been identified (6-12), and an immunodominant CTL epitope has been mapped in H-2.sup.d mice to residues 315-329, a highly variable region of the envelope (13). However, immunizing with the whole envelope protein is not an ideal approach for several reasons. First, the majority of the cytotoxic response assayed in vitro with fresh PBMC from HIV seropositive individuals seems to be mediated by non-MHC restricted mechanisms (ADCC or NK) (14). Second, the envelope is highly variable in sequence and CTL clones can distinguish different isolates of HIV (15,16). Third, there is evidence for antibody-dependent enhancement of HIV-1 infection, likely to be mediated by anti-envelope antibodies (17,18). Fourth, immune responses to the HIV envelope have been suggested to contribute to immune deficiency: Uninfected CD4+ T cells which bind gp120 may be killed by ADCC triggered by anti-envelope antibodies (19) or by CD4+ CTL specific for gp120 (20). Anti-gp120 antibodies can also inhibit CD4+ T-cell function like anti-CD4 antibodies by binding to gp120 which binds to CD4 (21). Also, gp160 can elicit autoantibodies that crossreact with human Class II MHC molecules and inhibit T-cell function (22). Finally, gp120 itself may inhibit T-cell function directly (19).
In contrast to the envelope glycoprotein, the internal proteins of HIV are more conserved and would be less likely to contribute to these deleterious effects. Moreover, in other vital models, internal proteins are the predominant targets of the CTL response (23-28). Responses have been found in HIV patients against the products of the gag, pol, nef and vif genes (7,9,12,-29,30). Because of its conservation and importance to vital function, the reverse transcriptase (RT) appears worthy of particular interest in this regard. We describe here our approach of using a murine model to identify evolutionarily conserved CTL determinants in RT and the relevance of this identification to human anti-HIV cytotoxic responses.